Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Yoshikuni Mimata, Akihisa Kamataki, Shinya Oikawa, Kenya Murakami, Miwa Uzuki, Tadashi Shimamura, Takashi Sawai
International Journal of Rheumatic Diseases 2012, 15 (1): 36-44

AIM: A disintegrin-like and metalloproteinase with thrombospondin type 1 motif (ADAMTS)-4 and ADAMTS-5 play crucial roles in the cleavage of aggrecan. Several recent studies have demonstrated the effect of cytokines such as interleukin (IL)-1β, tumor necrosis factor-α and transforming growth factor-β on the expression of ADAMTS-4 and ADAMTS-5 in fibroblast-like synoviocytes (FLS). However, the effect of IL-6 remains unclear. The aim of this study is to investigate the expression of ADAMTS-4 and ADAMTS-5 in FLS of rheumatoid arthritis (RA) patients after IL-6 stimulation.

METHOD: Immunohistochemical staining was performed to examine the expression and localization of ADAMTS-4 and ADAMTS-5 in RA synovium. FLS isolated from RA patients were stimulated by IL-6 and soluble IL-6 receptor (sIL-6R) in the presence or absence of anti-IL-6R antibody, and the expression levels of ADAMTS-4 and ADAMTS-5 messenger RNA (mRNA) were assessed using real-time polymerase chain reaction. Furthermore, the IL-6 signaling pathway for regulation of ADAMTS-4 and ADAMTS-5 was also examined.

RESULTS: Staining for ADAMTS-4 and ADAMTS-5 was mainly observed in the sublining layer of synovial membrane and pannus. The expression of ADAMTS-4 mRNA was increased by IL-6/sIL-6R, whereas that of ADAMTS-5 was decreased. Anti-IL-6R antibody suppressed the effect of IL-6/sIL-6R. Mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) kinase (MEK)1/2 inhibitor U0126 inhibited the effect of IL-6/sIL-6R on ADAMTS-4 mRNA expression in FLS. Signal transducer and activator of transcription 3 (STAT3) inhibitor parthenolide inhibited the effect of IL-6/sIL-6R on ADAMTS-4, and downregulated ADAMTS-5 expression.

CONCLUSION: These results suggest IL-6 may participate in cartilage destruction in RA as an inducer of ADAMTS-4 expression from FLS.

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